Malaria remains a number one killer disease in the world with more than 200 million people infected, and half a million deaths every year. This is no effective vaccine and the emergence of drug resistance prevents efficient malaria control. Further investigations are needed and of high priority to better understand this important parasitic disease and its severe forms in order to improve clinical outcomes. Data from human and mouse studies suggests that the immunomodulatory cytokine type I IFN and its signaling is associated with malaria disease outcome. Type I IFN exhibits very broad immunomodulatory properties and profound effects on innate and adaptive immune cell activation and programming. Plasmacytoid dendritic cells (pDCs) are the most specialized cell subset in producing type IFN, and can secrete up to a 1,000 times more abundant levels of type I IFN than any other cell type. Using the Plasmodium yoelii surrogate mouse model of lethal malaria infection that recapitulates many features of human severe malaria, we have established type I IFN as an essential early mediator of immune cell activation that can modulate disease outcomes. We discovered that BM macrophages through functional and physical interactions control pDC activation. In this proposal, we seek to understand the molecular mechanisms underlying this interaction.